For many patients, organ transplantation remains the only form of treatment for their disease. However, immunological rejection of grafted organs of fatal graft vs host (GVH), which may accompany marrow reconstitution, have limited the potentiality of organ replacement as a therapeutic tool. The most direct means to establish organ replacement as a therapeutic tool is to define conditions by which tolerance to major as well as minor histocompatibility alloantigens could be achieved and maintained. Although a number of avenues to attain tolerance are being examined by various investigators, we will concentrate in this application on means of inducing tolerance to bone marrow cells in a manner so that the accompanying GVH that usually results after reconstitution with marrow cells is avoided. Generally the most successful reconstitution of animals (and patients) is achieved with bone marrow obtained from a donor that is identical with the recipient at the major histocompatibility locus--the H-2 complex of the mouse and the HLA complex of man. In recent experiments of our own, we have observed that the transfer of bone marrow cells from one strain of mouse into a lethally x-irradiated H-2 (K-end) disparite strain did not results in fatal GVH for a period of over 300 days in 6 out of 10 animals injected, a finding which is opposite of what we expected. Reconstitution of mice of a different strain, which had the same H-2 haplocyte as the first recipients, however, did succumb as expected in a rather short period after reconstitution. Our long range goals of the research proposed herein, therefore, are to utilize the mouse system to: (1) define the parameters, i.e., genetic or environmental, which determine the different mean survival times in the two H-2 identical strains of mice after reconstitution with H-2 disparite bone marrow cells; (2) determine the mechanism by which death is avoided; and (3) assess the usefulness of the mechanism underlying our findings in mice for the reduction of tolerance to marrow grafts in man.